A small interfering RNA (hereinafter referred to as siRNA) is involved in the RNA interference (hereinafter referred to as RNAi) and is an RNA having a function as a guide for inhibiting the expression of a target gene [Nature, vol. 411, No. 6836, pp. 494-498]. An siRNA can selectively inhibit (knock down) the expression of the protein which a messenger RNA (mRNA) regulates, through cleavage of the mRNA, and therefore, the application thereof to pharmaceuticals is expected (Nature Reviews Cancer, vol. 11, pp. 59-67, 2011).
An siRNA is generally incorporated into a complex called an RNA induced silencing complex (RISC), and then exhibits its function. A main constituent component of the RISC is a protein called Argonaute 2 (AGO2), and AGO2 binds to an siRNA in the RNAi pathway and cleaves an mRNA (Trends in Biochemical Sciences, vol. 35, No. 7, pp. 368-376, 2010). The siRNA incorporated into the RISC is converted to a single strand of only the antisense strand by cleaving the sense strand, and thereafter binds to a target mRNA complementary to the antisense strand. It is known that the target mRNA is then cleaved by an RNAse domain in the AGO2, resulting in inhibiting the expression of the protein (Silence, vol. 1, p. 3, 2010).
On the other hand, in recent years, three-dimensional structure analysis of hAGO2 MID/AMP complex and hAGO2 MID/UMP complex (Nature, vol. 465, pp. 818-822, 2010), and a three-dimensional structure analysis for a complex of hAGO2 and an RNA oligonucleotide (Science, vol. 336, p. 25, 2012) have also been reported.
Further, in recent years, particularly a structural analysis of proteins using an X-ray is actively carried out, and there have been many reports of attempts to elucidate a mode of binding between a protein and a compound targeting the protein at the atomic level on the basis of the obtained structural information and to design a compound which fits the structure (Journal of Postgraduate Medicine, vol. 55, pp. 301-304, 2009).
However, although a possibility of avoiding an off-target effect (Patent Literature 1) and a possibility of enhancing the activity of an siRNA by improving the affinity for AGO2 (Non Patent Literature 1) using an oligonucleotide containing an unnatural nucleotide are suggested, a specific method for improving the affinity for AGO2 and enhancing the knockdown activity is not disclosed.